The human nervous system develops by selecting appropriately connected nerve cells for survival. More nerve cells (neurons) are born than are needed, and the neurons that don't make the right connections activate a cell suicide program, programmed cell death. The connecting cell sends a signal to deactivate programmed cell death when a neuron makes a correct connection. This signal is a polypeptide growth factor, or neurotrophin, of which nerve growth factor (NGF) is the best studied. NGF binds to its receptor (TrkA), and both are internalized together and transported down the long processes of nerve cells (axons) back to the cell body, where the nucleus resides, to change gene expression to turn off programmed cell death. The vehicle for the transport of NGF and TrkA is the signaling endosome, a membrane-bound organelle. Signaling endosomes are formed at axon tips, where target-derived neurotrophins are secreted and first encounter receptors. The endosomes travel from axon tips to the cell body, where the receptors in these endosomes initiate signaling mechanisms that turn off apoptosis and cause differentiation into a mature neuron. The membrane traffic mechanisms that form signaling endosomes are not well understood. We hypothesize that signaling endosomes are specialized, long-lived organelles that are distinct from canonical endosomes in the recycling and degradative pathways. The experiments proposed here test the hypothesis that neural cells have unique sorting mechanisms and components that give them the ability to make neurotrophin-responsive signaling endosomes. [unreadable] [unreadable]